Current Treatment Options for REM Sleep Behaviour Disorder

The symptomatic treatment of REM sleep behaviour disorder (RBD) is very important to prevent sleep-related falls and/or injuries. Though clonazepam and melatonin are usually considered the first-line symptomatic therapy for RBD, their efficiency has not been proven by randomized clinical trials. The role of dopamine agonists in improving RBD symptoms is controversial, and rivastigmine, memantine, 5-hydroxytryptophan, and the herbal medicine yokukansan have shown some degree of efficacy in short- and medium-term randomized clinical trials involving a low number of patients. The development of potential preventive therapies against the phenoconversion of isolated RBD to synucleinopathies should be another important aim of RBD therapy. The design of long-term, multicentre, randomized, placebo-controlled clinical trials involving a large number of patients diagnosed with isolated RBD with polysomnographic confirmation, directed towards both symptomatic and preventive therapy for RBD, is warranted.


Introduction
The first reports of the disorder designated as "rapid eye movement (REM) sleep behaviour disorder" (RBD) were by Schenk et al. [1,2] in 1986. This new type of parasomnia, which was seen in patients with different neurological disorders (most of them were men), shared some similarities with a behavioural disorder found in cats with pontine tegmental lesions during REM sleep and was described as "abnormal behaviours during REM sleep such as stereotypical hand motions, reaching and searching gestures, punches, kicks, and verified dream movements". Polysomnography (PSG), which is considered to be necessary for the definitive diagnosis of RBD [3], is characterized by a loss of chin atonia in variable degrees, increased REM ocular activity, increased REM limb-twitch activity, and increased density and duration of stage 3-4 slow-wave sleep.
According to their aetiology, RBD can be classified as "idiopathic" or "isolated" (iRBD; this diagnosis requires a lack of evidence of any diagnosed neurological disease) or secondary to narcolepsy, neurodegenerative diseases, drugs, or autoimmune disorders [4,5]. Structural lesions affecting the medulla, the pons, or the limbic system have also been reported as a cause of secondary RBD [6][7][8]. The long-term follow-up of patients initially classified as iRBD has shown the development of neurodegenerative diseases, mainly synucleinopathies such as Lewy body dementia (LBD), Parkinson's disease (PD), or multisystem atrophy (MSA) [9]. Probable iRBD (that is, iRBD diagnosed on clinical grounds without PSG confirmation) is a high-prevalence disorder, with an estimated frequency of 5.65 (95% CI = 4.29-7.18%) according to a recent meta-analysis [10].
The aetiology of iRBD is largely unknown, although associations with an hexanucleotide repeat expansion in the C9orf72-SMCR8 complex subunit (C9orf72) gene [11], missense variations in the glucosylceramidase beta glucocerebrosidase (glucocerebrosidase or GBA) gene [12], and some rare variants in the bone marrow stromal cell antigen 1 (BST1) and lysosomal-associated membrane protein 3 (LAMP3) genes [13] have been described in some patients, and possible associations between smoking, farming, and previous head injuries to the risk for iRBD have been suggested [14].
The neurochemical features of RBD include dopaminergic deficiency (the most consistent finding) and changes in noradrenaline, acetylcholine, excitatory and inhibitory neurotransmitters, hormones such as melatonin, and proinflammatory factors [15]. Patterns resembling those of PD and/or LBD have been found in brain glucose metabolism and brain perfusion studies, and cortical grey matter atrophy, structural changes in deep grey matter nuclei, and alterations in the functional connectivity between several networks including the basal ganglia and cerebral cortex have been found by using structural and functional MRI [15].
Despite the assumption that the first-line drugs in the therapy or RBD are clonazepam and melatonin, an ideal treatment has not been established. The aim of this narrative review is to provide a description of studies reported to date related to the treatment of this clinical entity.

Clonazepam
The improvement of RBD symptoms in patients treated with clonazepam (a benzodiazepine that enhances the neurotransmitter gamma-aminobutyric acid (GABA) via the modulation of the GABA A receptor and has antiepileptic properties) was suggested in the first description of RBD by Schenck et al. [1]. Table 1 summarizes the studies describing the effect of clonazepam in patients with RBD [1,2,[17][18][19][20][21][22][23][24][25][26][27][28]. Surprisingly, despite clonazepam being considered a first-line therapy for RBD (and according to the experience of the authors of this review, it is a useful drug for treating this condition), its efficacy in the treatment of iRBD has apparently not been proven in randomized trials. As shown in Table 1, reports on the efficacy of clonazepam in iRBD should be classifiable as possessing levels II or III of evidence. In a randomized doubleblind placebo-controlled clinical trial (level I of evidence, >50% of quality), Shin et al. [26] showed a similar degree of improvement in the RBD symptoms of PD patients with RBD between clonazepam at low doses (0.5 mg/day) and a placebo.
In a study involving 36 patients diagnosed with RBD treated with clonazepam as the first-line therapy, 58% developed moderate to severe side-effects, the most frequent being daytime sedation, confusion, and cognitive impairment [29]. It has been suggested that these side effects could increase the risk of falling and fall-related injuries in elderly patients [30]. In addition, it has been reported that clonazepam could induce or aggravate sleep apnoea syndrome in some patients [31].
Anderson et al. [29] reported the efficacy and tolerance of the cyclopyrrolone zopiclone (at 3.75-7.5 mg at night, alone or in combination, this drug increases GABAergic transmission by modulating benzodiazepine receptors) in 8 of 11 patients with side effects of clonazepam (level III of evidence) in an open-label study.

Melatonin and Its Analogues
Data from publications regarding the efficacy of the pineal hormone melatonin in RBD are summarized in Table 2 [21,27,[32][33][34][35][36][37][38][39][40][41][42][43]. Melatonin secretion has been reported as delayed by 2 h in patients with RBD [44]. Together with clonazepam, melatonin is considered to be a first-line therapy for RBD. 14 patients with secondary RBD treated with 3-12 mg/day of melatonin because of lack of response to (n = 6) or severe side-effects with clonazepam (n = 2), cognitive impairment (n = 6), or presence of severe obstructive sleep apnoea (n = 1) and narcolepsy (n = 1) Open-label trial. In 7 patients, melatonin was used as add-on therapy to 0.5-1 mg/day of clonazepam • Symptomatic control in 6 patients, significant improvement in 4, initial improvement with further worsening in 2, lack of improvement in 1, and increased severity of RBD in 1.

•
Effective melatonin doses: 3 mg (n = 2), 6 mg (n = 7), 9 mg (n = 1), and 12 mg (n = 2) • Side-effects in 5 patients resolved with decreasing doses (2 with morning headaches or sleepiness and 1 with delusions/hallucinations.   Most reports suggesting improvements of RBD with melatonin have been single case reports, open-label trials, or retrospective analyses of cohorts (therefore classifiable as level II or level III of evidence) [21,27,[32][33][34][35][36][37][38][39][40]43]. Only three studies were randomized clinical trials with level I of evidence and a quality rate >50%, one of them involving a short series of eight patients treated with 3 mg of melatonin at night who showed significant clinical and PSG improvement of RBD [37] and the other two involving 30 patients treated with 2-6 mg/day of prolonged release melatonin who both showed a lack of improvement of RBD [41,42].
The atypical antidepressant drug agomelatine acts as agonist of the melatonin receptors MT 1 and MT 2 , and the antagonist of the serotonin (5-hydroxytryptamine or 5-HT) 5-HT 2C and 5-HT 2B receptors. Bonakis et al. [45] reported the total or partial improvement of RBD symptoms in three patients with iRBD ( Table 3).
The efficacy of ramelteon, a melatonin receptor agonist with a high affinity for MT 1 and MT 2 receptors and selectivity over the MT 3 receptor, in the treatment of RBD has been reported in two patients with RBD associated with MSA [46] and in an open-label trial of patients with PD (68.6% of them with concomitant RBD; level II of evidence) [47]. However, another open-label trial failed to find significant improvement in patients diagnosed with RBD [48]. The results of studies with agomelatine and ramelteon are summarized in Table 3.

Dopamine Acting Drugs
The results of studies addressing the possible efficacy of dopaminergic drugs in the treatment of RBD are summarized in Table 4. Improvements of RBD symptoms with levodopa in three patients with RBD and preclinical PD [49] and in a patient with LBD and concomitant RBD have been described [50].   While three open-label studies (level-II of evidence) [51,52,54] and a retrospective cohort involving 81 patients with iRBD (level-II of evidence) [55] showed a beneficial effect of pramipexole (a D 2 and D3 non-ergoline dopamine receptor agonist with D 3 -preferring receptor-binding profile) in 60-80% of patients diagnosed with iRBD, another open-label study (level-II of evidence) showed a lack of improvement of RBD symptoms in 11 patients with PD and concomitant RBD treated with low doses of this drug as add-on therapy to levodopa [53]. In contrast, another open-label study (level-II of evidence) involving 11 patients with PD and RBD showed a beneficial effect of the dopamine agonist rotigotine (a non-ergoline and non-selective agonist of the dopamine D 1 , D 2 , D 3 , and (to a lesser extent) D 4 and D 5 receptors, with the highest affinity for the D 3 receptor) at relatively higher doses [56].
On the other hand, a recent study involving 250 patients diagnosed with idiopathic PD who completed a RBD Screening Questionnaire (RBDSQ) [58] showed an association between RBDSQ scores and the doses of levodopa used (while no association was found with dopamine agonists), although it could not be excluded that this result may have been related to the PD duration and/or severity [59]. Previously, Ozekmekçi et al. [60] reported that, compared to PD patients without RBD, patients with RBD showed higher duration of the disease and higher current doses of levodopa, a finding that could suggest a relationship between the cumulative doses of levodopa and the development of RBD.
Finally, a recent longitudinal randomized cross-over study in with safinamide (a potent and selective monoamine oxidase B (MAOB) inhibitor that enhances dopaminergic neurotransmission and inhibits glutamate release and dopamine and serotonin reuptake) involving 30 patients with PD and RBD showed a significant clinical improvement of RBD symptoms in more than 70% [57].

Sodium Oxybate
Sodium oxybate, also named sodium 4-hydroxybutyrate and sodium 4-hydroxybutanoate, is the sodium salt of γ-hydroxybutyric acid, and it is used for the treatment of sudden muscle weakness and excessive daytime sleepiness in patients with narcolepsy. The results of reports on the treatment of RBD with sodium oxybate are summarized in Table 5. Some anecdotal reports described clinical improvements of RBD symptoms in patients with iRBD [61,62], RDB associated with PD [63], and narcolepsy type 1 [64]. A recent open-label trial involving 19 children and adolescents with RBD associated with narcolepsy type 1 (level II of evidence) also showed the clinical and PSG improvement of RBD symptoms [65].

Drugs Used for the Therapy for Alzheimer's Disease
Ringman and Simmons [66] reported the marked and prolonged improvement of RBD symptoms in three patients with AD and RBD after starting treatment with 10-15 mg/day of the cholinesterase inhibitor donepezil. In addition, two short-term double-blind crossover pilot studies (level I of evidence; >50% of quality score) showed improvements of RBD symptoms resistant to clonazepam and melatonin in patients with RBD associated with PD [67] and mild cognitive impairment [68], respectively, with 4.6 mg/day of the cholinesterase inhibitor rivastigmine (Table 6). Interestingly, a case of RBD induced by rivastigmine in a patient diagnosed with AD was reported [69].   1% of them receiving yokukansan as add-on therapy were "responders" ("very much improved" and "much improved"). A recent double-blinded placebo-controlled randomized multicentre trial (level I of evidence; quality score >50%; see Table 6) showed a beneficial effect of memantine [83]. This drug is a low-affinity, voltage-dependent, non-competitive antagonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptors, a non-competitive antagonist of the 5-HT 3 receptor, antagonist of several neuronal nicotinic acetylcholine receptors (nAChRs), and agonist of the D 2 receptors.
Nelotanserin (a drug primarily developed for the treatment insomnia that acts as an inverse agonist on the serotonin receptor subtype 5-HT 2A ) at a dose of 80 mg/day was tested in a short-term double-blind placebo-controlled randomized multicentre trial (level I of evidence; >50% of quality score) in patients with RBD associated with DLB or PD-dementia (PDD); negative results were reported [74].
Finally, a recent short-term randomized double-blind placebo-controlled crossover trial showed a beneficial effect of 5-hydroxytryptophan (the precursor of serotonin) in the treatment of RBD symptoms in patients with PD and RBD (level I of evidence; >50% of quality score) [75].

Antiepileptic Drugs
The effects of antidepressants and/or serotoninergic drugs on RBD are summarized in Table 6. Studies have reported marked improvements of RBD symptoms in one patient with iRBD treated with carbamazepine [76] and one patient with RBD associated with probable LBD treated with levetiracetam [77]. To our knowledge, there has been no report of possible improvements of RBD with lamotrigine, but the worsening of RBD symptoms in a patient diagnosed with iRBD related to lamotrigine withdrawal was described [84].
Potassium bromide (K Br), a salt that was widely used as an antiepileptic and sedative in the late 19th and early 20th centuries and is used as an antiepileptic medication for dogs, was shown to be effective in the treatment of RBD-like symptoms in 14 dogs [85]

Cannabinoids
The effects of antidepressants and/or serotoninergic drugs on RBD are summarized in Table 6. Cannabidiol is a phytocannabinoid that acts an antagonist of the cannabinoid CB 1 and CB 2 receptors, with a low affinity for them. Following the description of short-term improvements of RBD symptoms in four patients with PD and RBD [78], a randomized placebo-controlled clinical trial involving 33 patients with PD and RBD (level I of evidence; quality score >50%) showed improvement in sleep satisfaction but not significant differences in the control of RBD at two different doses of cannabidiol compared with placebo [79].

Herbals
The effects of antidepressants and/or serotoninergic drugs on RBD are summarized in Table 6. The herbal medicine yokukansan or Yi-Gan San has led to improvements of RBD symptoms in a short case series [80] and two retrospective analyses of clinical records [81,82] (in one of them via a comparison with clonazepam [82]).

Non-Pharmacological Therapies
Howell et al. [86] showed a decrease in RBD symptoms and sleep-related injuries in four patients diagnosed with RBD resistant to clonazepam and melatonin therapy by using customized bed alarms with a familiar voice to deliver a calming message at the onset of dream enactment behaviours (level III of evidence) based on complex auditory processing and the low arousal threshold of REM sleep.
Finally, McCarter et al. [87] speculated that high-intensity exercise could have a protective role in the development of Parkinsonism in patients initially diagnosed with iRBD based on the attenuation of the symptomatic progression of PD and the delayed onset of AD with high-intensity exercise in humans, as well as the demonstration of a reduction of accumulation of α-synuclein, tau protein, and amyloid beta in animals by exercise.

Discussion and Conclusions
The search for appropriate treatments for RBD is important for preventing sleeprelated injuries of both patients and their partners. In addition, due to the high described rate of the phenoconversion of iRB to synucleinopathies, it is important to try potential preventive therapies following the early detection of patients at risk. However, the ideal therapy for RBD is not currently established. Traditionally, clonazepam and melatonin have been used as first-line treatments based on the descriptions of improvements of RBD symptoms of many patients treated with these drugs in single case reports, case series, retrospective medical reports, and open-label trials (Tables 1 and 2). However, only one randomized clinical trial addressing the effects of clonazepam versus placebo in PD patients with RBD failed to find significative differences between clonazepam and placebo [26]; another randomized clinical trial involving a small number of patients that compared 3 mg of standard-release melatonin with placebo found a higher degree of improvement with melatonin, and two other shorter randomized clinical trials showed a similar efficacy of prolonged-release melatonin (2, 4, and 6 mg) compared to placebo in improving RBD symptoms [41,42].
The possible efficacy of analogues of melatonin (Table 3), levodopa, and dopamine agonists ( Table 4) has not been established and is controversial, although a large retrospective cohort study (level II of evidence) suggested an improvement in 61.7% of iRBD non-responders to clonazepam with pramipexole therapy. Moreover, one must consider the possibility that levodopa at high doses could be related to the risk of developing RBD in PD patients [56]. Safinamide could be useful in the treatment of RBD associated with PD according to a recent longitudinal randomized clinical trial involving a small number of patients [57].
Results of randomized clinical trials, most of them involving a limited number of patients, have shown the short-term efficacy of the anticholinesterase drugs rivastigmine [67,68] and 5-hydroxytryptophan [75] and the herbal medicine yokukansan [81,82], as well as the lack of efficacy of nelotanserin [74] and cannabidiol [79]. Memantine has shown some degree of medium-term efficacy in the reduction of RBD symptoms in patients with LBD and dementia associated with PD [83].
The results of this review are, in general, in agreement with those of other previous reviews [88][89][90][91][92][93][94][95][96][97][98]. Ideally, the design of therapeutical trials for RBD should pursue two main types of objectives: the adequate symptomatic therapy for RBD symptoms and the possibility of developing neuroprotective (preventive) strategies. Symptomatic therapy should be developed to prevent sleep-related falls and injuries and to improve the quality of sleep of the patients, while the development of neuroprotective therapies, at least in patients with higher risks of developing synucleinopathies) could be used to delay the clinical onset and improve the clinical course of these diseases.
For both types of studies, the design should be prospective and multicentre, involved a large series of patients diagnosed with iRBD with polysomnographic confirmation, and possessing a large follow-up period. Studies on symptomatic therapies should be randomized, double-blind, and placebo-controlled, and they could include several active pharmacological branches including clonazepam, melatonin, and other drugs that have shown any possibility of improving RBD symptoms in non-controlled trials or in cohort studies. Follow-up evaluation should include sleep diary, well-validated scales for RBD symptoms, the use of actigraphy devices, and at least one basal PSG study at the start and end of the follow-up.
Given the facts that PD is a very common neurological disorder and RBD is frequently associated with it before the onset of motor symptoms, it seems reasonable studies looking for neuroprotective strategies should include a selection of patients with polysomonographically confirmed iRBD and neurochemical and/or neuroimaging markers that suggest a high-risk of phenoconversion to synucleinopathies [15,91,97,99]. The combination of functional neuroimaging studies using different tracers, transcranial sonography, brain per-fusion and glucose metabolism studies, functional MRI, and the detection of α-synuclein in certain tissues should be useful for this purpose [15]. Funding: The work at the authors' laboratory was supported in part by grants PI15/00303, PI18/00540, and RETICS RD16/0006/0004 from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spain, and GR18145 and IB20134 from Junta de Extremadura, Spain. This study was financed in part with FEDER funds from the European Union.
Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.